Recent preclinical and clinical studies suggest that the glutamatergic system is involved in the mechanism of action of antidepressants. We found that the non-competitive NMDA antagonist (ketamine) was effective in treatment-resistant major depression. Ketamine resulted in rapid, robust and relatively sustained antidepressant effects. Response with ketamine occurred within 2 hours and last approximately 1 week. The current protocol consists of 3 primary studies designed to address 3 major questions, study 2 and 3 are still ongoing and subjects are actively being recruited to participate in these studies: Study 1 (Rapid improvement research in unipolar depression) OBJECTIVE: To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression. DESIGN: A randomized, placebo-controlled, double-blind crossover study. SETTING: Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects with DSM-IV major depression (treatment resistant). INTERVENTIONS: After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. RESULTS: Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 95% confidence interval, 0.91-2.01) after 24 hours and moderate to large (d = 0.68 95% confidence interval, 0.13-1.23) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. CONCLUSIONS: Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist;onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. Study 2 (Rapid improvement research in bipolar depression) Does the NMDA antagonist ketamine produce rapid antidepressant effects in patients with treatment-resistant bipolar depression? Patients ages 18 to 65 years with treatment-resistant bipolar depression are actively being recruited in a double-blind crossover study and are receiving either intravenous ketamine or saline solution added to a mood stabilizer (lithium or valproate). The efficacy component of the study is completed and the data are being analyzed. The study remains open for active recruitment as more subjects are required to complete the neurophysiological (MEG, PSG, PET substudies) in search of biomarkers of response. Study 3 (Rapid and sustained improvement research in unipolar depression) Does riluzole (an inhibitor of glutamate release) prevent relapse in patients with treatment-resistant major depression who have rapidly responded to a single intravenous dose of ketamine. Patients ages 18 to 65 years with treatment-resistant major (unipolar) depression who have rapidly responded to a single intravenous dose of ketamine are then randomized to receive in a double-blind study either riluzole or placebo to determine if the rapid response obtained can be sustained. The study is still actively recruiting study participants. The results from this study are not yet available because the study has not yet been completed. Our primary hypotheses for these studies are: 1) rapid response (same or next day) can be achieved in patients with treatment-resistant major (unipolar) depression, 2) rapid response (same or next day) can be achieved in patients with treatment-resistant bipolar depression, and 3) rapid response (same or next day) can be sustained in patients with treatment-resistant unipolar depression. Other aims of this study are 1) to examine the antisuicidal effects of ketamine, and 2) to examine correlates of antidepressant response to ketamine in both major depressive disorder and bipolar disorder and include: clinical (e.g., family history), imaging (positron emission tomography PET, magnetic resonance imaging/spectroscopy), electrophysiological (magnetoencephalography MEG, electroencephalography EEG), neuropsychological, and biochemical (e.g., genetics, microRNA, BDNF, metabolomics). Results in the past year: 1) Rapid Resolution of Suicidal Ideation Occurs after a Single Infusion of an NMDA Antagonist in Patients with Treatment-Resistant Major Depressive Disorder (DiazGranados et al. in press): Objective: Suicidal ideation is a medical emergency, especially when severe. Little research has been done on pharmacological interventions that could address this problem. Ketamine, an N-methyl-D-aspartate (NMDA) antagonist, has been reported to have antidepressant effects within hours. We examined the effects of a single dose of ketamine on suicidal ideation in subjects with treatment-resistant major depressive disorder (MDD).Method: Thirty-three subjects with DSM-IV-diagnosed MDD received a single open-label infusion of ketamine (0.5 mg/kg) and rated at baseline, 40, 80, 120, and 230 minutes post-infusion with the Scale for Suicide Ideation (SSI), the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale (HDRS), and the Beck Depression Inventory (BDI). Results: Suicidal ideation scores decreased significantly on the SSI as well as on the suicide subscales of other rating instruments within 40 minutes;these decreases remained significant through the first four hours post-infusion (p<.001). Conclusion: Suicidal ideation in the context of MDD improved within 40 minutes of a ketamine infusion and remained improved for up to four hours post-infusion. Future studies with ketamine in suicidal ideation are warranted due to its potential impact on public health. 2) Family history of alcohol dependence predicts initial antidepressant response to an N-methyl-D-aspartate antagonist (Phelps et al. 2009). Subjects with a family history of alcohol dependence showed significantly greater improvement in MADRS scores compared with subjects who had no family history of alcohol dependence. 3) Increased anterior cingulate cortical activity in response to fearful faces is a neurophysiological biomarker that predicts rapid antidepressant response to ketamine (Salvadore et al. 2009): Most patients with major depressive disorder (MDD) experience a period of lengthy trial and error when trying to find optimal antidepressant treatment;identifying biomarkers that could predict response to antidepressant treatment would be of enormous benefit. Patients with MDD showed robust increases in pretreatment anterior cingulate cortex (ACC) activity positively correlated with subsequent rapid antidepressant response to ketamine. Pretreatment rostral ACC activation may be a useful biomarker that identifies a subgroup of patients who will respond favorably to ketamine's antidepressant effects. 4) Brain-Derived Neurotrophic Factor is not involved in the Initial Antidepressant Response to an N-Methyl-D-Aspartate Antagonist. Despite a significant (P <.001) improvement in MADRS scores after subjects received ketamine treatment, no changes in BDNF levels were observed in subjects after they received ketamine compared to baseline. Also, no association was found between antidepressant response and BDNF levels. This study demonstrates that ketamines rapid initial antidepressant effects are not mediated by BDNF. Further studies are necessary to shed light on the neurobiological basis of these effects.